Trial Outcomes & Findings for Study of Mapatumumab in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma (NCT NCT01258608)

Last Updated: 2018-12-19

Results Overview

Time to progression is defined as the time from randomization to radiologic disease progression based on blinded independent review (BICR) of imaging scans using modified Response Evaluation Criteria in Solid Tumors assessment (mRECIST) for hepatocellular carcinoma. The primary analysis was performed using Kaplan Meier methods. The median time to progression is reported with one-sided 90% confidence interval. Analysis was performed on the modified Intent to Treat (mITT) Population which comprised of all randomized participants who received at least part of 1 dose of study agent (mapatumumab/placebo and/or sorafenib) with participants analyzed according to the groups to which they were randomized. NA indicates upper limit was not measurable as one-sided confidence interval is presented.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

101 participants

Primary outcome timeframe

Randomization to maximum of 24.1 months

Results posted on

2018-12-19

Participant Flow

This was a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of mapatumumab in combination with sorafenib in participants with advanced hepatocellular carcinoma.

A total of 217 participants were screened of which 116 were screen failures and 101 participants were randomized in a ratio of 1:1 to any one of the 2 treatment arms. The study was conducted at 29 centers in 6 countries.

Participant milestones

Participant milestones
Measure	Sorafenib+Placebo Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity.
Overall Study STARTED	51	50
Overall Study COMPLETED	30	31
Overall Study NOT COMPLETED	21	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Sorafenib+Placebo Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity.
Overall Study Metastatic Hepatocellular Carcinoma	1	0
Overall Study Clinical progression	1	0
Overall Study Sponsor decision	0	1
Overall Study Physician Decision	6	1
Overall Study Lost to Follow-up	0	1
Overall Study Lack of compliance	1	0
Overall Study Lack of Efficacy	0	1
Overall Study Adverse Event	6	10
Overall Study Withdrawal by Subject	6	5

Baseline Characteristics

Study of Mapatumumab in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Total n=101 Participants Total of all reporting groups
Age, Continuous	60.8 Years STANDARD_DEVIATION 13.36 • n=5 Participants	60.0 Years STANDARD_DEVIATION 11.93 • n=7 Participants	60.4 Years STANDARD_DEVIATION 12.62 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	24 Participants n=7 Participants	36 Participants n=5 Participants
Sex: Female, Male Male	39 Participants n=5 Participants	26 Participants n=7 Participants	65 Participants n=5 Participants
Race/Ethnicity, Customized White/Caucasian - European Heritage	48 Participants n=5 Participants	48 Participants n=7 Participants	96 Participants n=5 Participants
Race/Ethnicity, Customized Asian-East Asian Heritage	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: mITT Population. Only those participants who had their BICR scans read were included in the analysis.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=48 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=45 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Time to Progression-Blinded Independent Central Review (BICR) Assessment	5.6 Months Interval 4.3 to Upper limit was not measurable as one-sided confidence interval is presented	4.1 Months Interval 2.8 to Upper limit was not measurable as one-sided confidence interval is presented.

SECONDARY outcome

Timeframe: Randomization to maximum of 52.9 months

Population: mITT Population

Time to progression is defined as the time from randomization to radiologic disease progression. The primary analysis was performed using Kaplan Meier methods based on application of mRECIST for hepatocellular carcinoma to investigator assessments. The median time to progression is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Time to Progression-Investigator Assessment	8.3 Months Interval 5.4 to Upper limit was not measurable as one-sided confidence interval is presented.	6.4 Months Interval 5.4 to Upper limit was not measurable as one-sided confidence interval is presented.

SECONDARY outcome

Timeframe: Randomization to maximum of 52.9 months

Population: mITT Population

Overall survival is defined as time from randomization to death from any cause. The analysis was performed using Kaplan Meier methods. The median overall survival is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Median Overall Survival	10.1 Months Interval 8.9 to Upper limit was not measurable as one-sided confidence interval is presented.	10.0 Months Interval 7.3 to Upper limit was not measurable as one-sided confidence interval is presented.

SECONDARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: mITT Population. Only those participants who had their BICR scans read were included in the analysis.

Progression free survival is defined as time from randomization to radiologic disease progression or death from any cause. The analysis was performed using Kaplan Meier methods using BICR assessment of imaging scans. The median progression free survival is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=48 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=45 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Progression Free Survival-BICR Assessment	4.3 Months Interval 3.1 to Upper limit was not measurable as one-sided confidence interval is presented.	3.2 Months Interval 2.7 to Upper limit was not measurable as one-sided confidence interval is presented.

SECONDARY outcome

Timeframe: Randomization to maximum of 52.9 months

Population: mITT Population

Progression free survival is defined as time from randomization to radiologic disease progression or death from any cause. The analysis was performed using Kaplan Meier methods based on application of mRECIST for hepatocellular carcinoma to investigator assessments. The median progression free survival is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Progression Free Survival-Investigator Assessment	5.4 Months Interval 3.6 to Upper limit was not measurable as one-sided confidence interval is presented.	4.0 Months Interval 3.4 to Upper limit was not measurable as one-sided confidence interval is presented.

SECONDARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: mITT Population. Only those participants who had their BICR scans read and having available assessment for best response were analyzed.

Objective response rate is defined as the percentage of participants with complete response+partial response according to mRECIST criteria for hepatocellular carcinoma using BICR assessment of imaging scans. The percentage of participants with objective response is reported along with 95% confidence interval.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=40 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=39 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Percentage of Participants With Objective Response-BICR Assessment	12.5 Percentage of participants Interval 4.2 to 26.8	17.9 Percentage of participants Interval 7.5 to 33.5

SECONDARY outcome

Timeframe: Randomization to maximum of 52.9 months

Population: mITT Population. Only those participants with available assessment for best response were analyzed.

Objective response rate is defined as the percentage of participants with complete response+partial response according to mRECIST criteria for hepatocellular carcinoma to investigator assessments. The percentage of participants with objective response is reported along with 95% confidence interval.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=48 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Percentage of Participants With Objective Response-Investigator Assessment	7.8 Percentage of participants Interval 2.2 to 18.9	14.6 Percentage of participants Interval 6.1 to 27.8

SECONDARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: mITT Population. Only those participants who had their BICR scans read and having available assessment for best response were analyzed.

Disease control rate is the percentage of participants with complete response+partial response+stable disease according to mRECIST criteria for hepatocellular carcinoma. The end point was based on BICR assessment of imaging scans. The percentage of participants with disease control is presented along with 95% confidence interval.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=40 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=39 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Percentage of Participants With Disease Control-BICR Assessment	92.5 Percentage of participants Interval 79.6 to 98.4	71.8 Percentage of participants Interval 55.1 to 85.0

SECONDARY outcome

Timeframe: Randomization to maximum of 52.9 months

Population: mITT Population. Only those participants with available assessment for best response were analyzed

Disease control rate is the percentage of participants with complete response+partial response+stable disease according to mRECIST criteria for hepatocellular carcinoma to investigator assessments. The percentage of participants with disease control is presented along with 95% confidence interval.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=48 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Percentage of Participants With Disease Control-Investigator Assessment	74.5 Percentage of participants Interval 60.4 to 85.7	68.8 Percentage of participants Interval 53.7 to 81.3

SECONDARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: mITT Population. Only responders were included in the analysis.

Time to response is defined as time from randomization to first partial response or complete response in responders only. Complete Response (CR): Disappearance of intratumoral arterial enhancement in all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=5 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=7 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Time to Response-BICR Assessment	44 Days Interval 41.0 to 85.0	48 Days Interval 41.0 to 188.0

SECONDARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: mITT Population. Only responders were included in the analysis.

Duration of response is defined as time from first PR or CR to radiologic disease progression; in responders only. CR: Disappearance of intratumoral arterial enhancement in all target lesions. PR: At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the Baseline sum of the diameters of target lesions. Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=5 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=7 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Duration of Response-BICR Assessment	123 Days Interval 55.0 to 325.0	127 Days Interval 42.0 to 372.0

SECONDARY outcome

Timeframe: Start of study treatment to maximum of 52.9 months

Population: As-Treated Population

An AE is any unfavorable or unintended sign, symptom, or disease that is temporally associated with the use of a study agent but is not necessarily caused by the study agent. An SAE is an adverse event resulting in any of the following outcomes: death, life-threatening, inpatient hospitalization, prolongation of an existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or other medically important events that may jeopardize the participant or may require intervention to prevent one of the other outcomes mentioned before. A treatment-emergent AE is an AE that emerged during treatment, having been absent pre-treatment, or worsened relative to the pre-treatment state. As-Treated Population comprised of participants who received at least part of 1 dose of study agent analyzed according to the treatment that they actually received.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) Non-serious AEs	47 Participants	49 Participants
Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	27 Participants	21 Participants

SECONDARY outcome

Timeframe: Start of study treatment to maximum of 52.9 months

Population: As-Treated Population

An AE is any unfavorable or unintended sign, symptom, or disease that is temporally associated with the use of a study agent but is not necessarily caused by the study agent. Severity of AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life -threatening consequences; urgent intervention indicated. Grade 5 represents death related to AE. Severe AE is defined as AEs classified by investigator as severe (causing inability to carry out usual activities), life threatening or fatal using NCI-CTCAE Version 4.0 grading.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Number of Participants With Severe AEs	42 Participants	38 Participants

SECONDARY outcome

Timeframe: Enrolment to maximum of 52.9 months

Population: As-Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Blood samples were collected for the evaluation of following chemistry parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), amylase, bilirubin, gamma glutamyl transferase (GGT), calcium, potassium, magnesium, albumin, sodium and creatinine. Laboratory toxicities were graded based on the NCI-CTCAE version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life -threatening consequences; urgent intervention indicated. Number of participants with worst toxicity grades for any abnormalities observed in any chemistry parameters during the study is presented.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALT increased; Grade 0, n=51, 50	6 Participants	4 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALT increased; Grade 1, n=51, 50	30 Participants	28 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALT increased; Grade 2, n=51, 50	8 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALT increased; Grade 3, n=51, 50	7 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALT increased; Grade 4, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters AST increased; Grade 0, n=51, 50	1 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters AST increased; Grade 1, n=51, 50	23 Participants	20 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters AST increased; Grade 2, n=51, 50	10 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters AST increased; Grade 3, n=51, 50	16 Participants	20 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters AST increased; Grade 4, n=51, 50	1 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALP increased; Grade 0, n=51, 50	4 Participants	8 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALP increased; Grade 1, n=51, 50	31 Participants	26 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALP increased; Grade 2, n=51, 50	11 Participants	11 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALP increased; Grade 3, n=51, 50	5 Participants	5 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters ALP increased; Grade 4, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Amylase increased; Grade 0, n=51, 50	30 Participants	22 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Amylase increased; Grade 1, n=51, 50	9 Participants	17 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Amylase increased; Grade 2, n=51, 50	5 Participants	8 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Amylase increased; Grade 3, n=51, 50	6 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Amylase increased; Grade 4, n=51, 50	1 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Bilirubin increased; Grade 0, n=51, 50	12 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Bilirubin increased; Grade 1, n=51, 50	15 Participants	10 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Bilirubin increased; Grade 2, n=51, 50	17 Participants	16 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Bilirubin increased; Grade 3, n=51, 50	7 Participants	13 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Bilirubin increased; Grade 4, n=51, 50	0 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters GGT increased; Grade 0, n=51, 50	1 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters GGT increased; Grade 1, n=51, 50	10 Participants	13 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters GGT increased; Grade 2, n=51, 50	14 Participants	15 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters GGT increased; Grade 3, n=51, 50	23 Participants	18 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters GGT increased; Grade 4, n=51, 50	3 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypercalcemia; Grade 0, n=49, 47	37 Participants	37 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypercalcemia; Grade 1, n=49, 47	11 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypercalcemia; Grade 2, n=49, 47	1 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypercalcemia; Grade 3, n=49, 47	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypercalcemia; Grade 4, n=49, 47	0 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyperkalemia; Grade 0; n=51, 50	36 Participants	27 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyperkalemia; Grade 1; n=51, 50	2 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyperkalemia; Grade 2; n=51, 50	10 Participants	10 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyperkalemia; Grade 3; n=51, 50	0 Participants	7 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyperkalemia; Grade 4; n=51, 50	3 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypermagnesemia; Grade 0; n=51, 50	29 Participants	28 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypermagnesemia; Grade 1; n=51, 50	21 Participants	19 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypermagnesemia; Grade 2; n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypermagnesemia; Grade 3; n=51, 50	1 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypermagnesemia; Grade 4; n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypernatremia; Grade 0, n=51, 50	18 Participants	18 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypernatremia; Grade 1, n=51, 50	16 Participants	14 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypernatremia; Grade 2, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypernatremia; Grade 3, n=51, 50	16 Participants	15 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypernatremia; Grade 4, n=51, 50	1 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypoalbuminemia; Grade 0, n=51, 50	22 Participants	26 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypoalbuminemia; Grade 1, n=51, 50	10 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypoalbuminemia; Grade 2, n=51, 50	18 Participants	14 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypoalbuminemia; Grade 3, n=51, 50	1 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypoalbuminemia; Grade 4, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypocalcemia; Grade 0, n=50, 50	16 Participants	15 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypocalcemia; Grade 1, n=50, 50	8 Participants	14 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypocalcemia; Grade 2, n=50, 50	18 Participants	19 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypocalcemia; Grade 3, n=50, 50	6 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypocalcemia; Grade 4, n=50, 50	2 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypokalemia; Grade 0, n=51, 50	37 Participants	41 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypokalemia; Grade 1, n=51, 50	11 Participants	8 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypokalemia; Grade 2, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypokalemia; Grade 3, n=51, 50	1 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypokalemia; Grade 4, n=51, 50	2 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypomagnesemia; Grade 0, n=51, 50	30 Participants	35 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypomagnesemia; Grade 1, n=51, 50	19 Participants	13 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypomagnesemia; Grade 2, n=51, 50	2 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypomagnesemia; Grade 3, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hypomagnesemia; Grade 4, n=51, 50	0 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyponatremia; Grade 0, n=49, 47	40 Participants	32 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyponatremia; Grade 1, n=49, 47	5 Participants	10 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyponatremia; Grade 2, n=49, 47	2 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyponatremia; Grade 3, n=49, 47	2 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Hyponatremia; Grade 4, n=49, 47	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Lipase increased; Grade 0, n=51, 50	19 Participants	13 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Lipase increased; Grade 1, n=51, 50	5 Participants	6 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Lipase increased; Grade 2, n=51, 50	8 Participants	8 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Lipase increased; Grade 3, n=51, 50	16 Participants	17 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Lipase increased; Grade 4, n=51, 50	3 Participants	6 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Renal: Creatinine increased; Grade 0, n=51, 50	36 Participants	34 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Renal: Creatinine increased; Grade 1, n=51, 50	7 Participants	12 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Renal: Creatinine increased; Grade 2, n=51, 50	8 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Renal: Creatinine increased; Grade 3, n=51, 50	0 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-chemistry Parameters Renal: Creatinine increased; Grade 4, n=51, 50	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Enrolment to maximum of 52.9 months

Population: As-Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Blood samples were collected for assessment of the following hematology parameters: activated partial thromboplastin time (APTT), hemoglobin, international normalized ratio (INR), lymphocytes, neutrophils, platelets and white blood cells (WBC). Laboratory toxicities were graded based on the NCI-CTCAE version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life -threatening consequences; urgent intervention indicated. Number of participants with worst toxicity grades for any abnormalities observed in any hematology parameters during the study is presented.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Number of Participants With Worst Toxicity Grade-hematology Parameters APTT prolonged; Grade 0, n=51, 50	24 Participants	22 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters APTT prolonged; Grade 1, n=51, 50	19 Participants	24 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters APTT prolonged; Grade 2, n=51, 50	6 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters APTT prolonged; Grade 3, n=51, 50	2 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters APTT prolonged; Grade 4, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Anemia; Grade 0, n=51, 50	13 Participants	9 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Anemia; Grade 1, n=51, 50	23 Participants	22 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Anemia; Grade 2, n=51, 50	9 Participants	16 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Anemia; Grade 3, n=51, 50	6 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Anemia; Grade 4, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Hemoglobin increased; Grade 0, n=46, 44	46 Participants	44 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Hemoglobin increased; Grade 1, n=46, 44	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Hemoglobin increased; Grade 2, n=46, 44	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Hemoglobin increased; Grade 3, n=46, 44	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Hemoglobin increased; Grade 4, n=46, 44	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters INR increased; Grade 0, n=51, 50	2 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters INR increased; Grade 1, n=51, 50	35 Participants	30 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters INR increased; Grade 2, n=51, 50	12 Participants	14 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters INR increased; Grade 3, n=51, 50	2 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters INR increased; Grade 4, n=51, 50	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes decreased; Grade 0, n=51, 50	24 Participants	23 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes decreased; Grade 1, n=51, 50	3 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes decreased; Grade 2, n=51, 50	16 Participants	18 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes decreased; Grade 3, n=51, 50	8 Participants	8 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes decreased; Grade 4, n=51, 50	0 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes increased; Grade 0, n=51, 49	49 Participants	45 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes increased; Grade 1, n=51, 49	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes increased; Grade 2, n=51, 49	2 Participants	4 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes increased; Grade 3, n=51, 49	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Lymphocytes increased; Grade 4, n=51, 49	0 Participants	0 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Neutrophil count decreased; Grade 0, n=51, 50	39 Participants	37 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Neutrophil count decreased; Grade 1, n=51, 50	3 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Neutrophil count decreased; Grade 2, n=51, 50	8 Participants	7 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Neutrophil count decreased; Grade 3, n=51, 50	1 Participants	1 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Neutrophil count decreased; Grade 4, n=51, 50	0 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Platelets decreased; Grade 0, n=51, 50	21 Participants	21 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Platelets decreased; Grade 1, n=51, 50	12 Participants	16 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Platelets decreased; Grade 2, n=51, 50	10 Participants	6 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Platelets decreased; Grade 3, n=51, 50	7 Participants	5 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters Platelets decreased; Grade 4, n=51, 50	1 Participants	2 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters WBC decreased; Grade 0, n=51, 50	33 Participants	30 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters WBC decreased; Grade 1, n=51, 50	10 Participants	12 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters WBC decreased; Grade 2, n=51, 50	8 Participants	5 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters WBC decreased; Grade 3, n=51, 50	0 Participants	3 Participants
Number of Participants With Worst Toxicity Grade-hematology Parameters WBC decreased; Grade 4, n=51, 50	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Randomization to maximum of 24.1 months

Population: As-Treated Population. Only participants with an available immunogenicity assay were analyzed.

Blood samples were collected for the assessment of serum antibodies. The presence of anti-mapatumumab antibodies was assessed using a validated electrochemiluminescent immunoassay. The assay incorporated a tiered testing approach which used screening and confirmation steps. The anti-drug antibody (ADA) confirmed positive participants were separated into transient or persistent antibody positives. Persistent positive refers to positive immunogenic response at 2 or more assessments or at the final assessment. Transient positive refers to positive immunogenic response at only 1 assessment and negative at the final assessment.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=49 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Number of Participants With Anti-mapatumumab Antibodies Transient positive	6 Participants	—
Number of Participants With Anti-mapatumumab Antibodies Persistent positive	7 Participants	—
Number of Participants With Anti-mapatumumab Antibodies Negative	36 Participants	—

SECONDARY outcome

Timeframe: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)

Population: As Treated Population. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).

SBP and DBP were obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; Cycle 2 Day 1, n=46, 44	2.3 Millimeters of mercury (mmHg) Standard Deviation 14.13	2.2 Millimeters of mercury (mmHg) Standard Deviation 18.64
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 3 DAY 1, n=39, 35	6.0 Millimeters of mercury (mmHg) Standard Deviation 16.81	4.1 Millimeters of mercury (mmHg) Standard Deviation 13.66
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 4; DAY 1; n=33, 32	2.1 Millimeters of mercury (mmHg) Standard Deviation 15.57	5.3 Millimeters of mercury (mmHg) Standard Deviation 13.52
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 5 DAY 1; n=27, 26	1.7 Millimeters of mercury (mmHg) Standard Deviation 13.05	4.9 Millimeters of mercury (mmHg) Standard Deviation 16.42
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 6 DAY 1; n=24, 22	1.3 Millimeters of mercury (mmHg) Standard Deviation 12.14	5.1 Millimeters of mercury (mmHg) Standard Deviation 13.40
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 7 DAY 1; n=24, 22	-0.8 Millimeters of mercury (mmHg) Standard Deviation 11.02	5.0 Millimeters of mercury (mmHg) Standard Deviation 12.78
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 8 DAY 1; n=22, 21	-1.6 Millimeters of mercury (mmHg) Standard Deviation 11.48	5.2 Millimeters of mercury (mmHg) Standard Deviation 14.83
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 9 DAY 1; n=19, 16	1.2 Millimeters of mercury (mmHg) Standard Deviation 16.37	7.8 Millimeters of mercury (mmHg) Standard Deviation 13.98
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 10 DAY 1; n=18, 16	1.4 Millimeters of mercury (mmHg) Standard Deviation 16.57	4.5 Millimeters of mercury (mmHg) Standard Deviation 16.19
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 11 DAY 1; n=16, 15	2.4 Millimeters of mercury (mmHg) Standard Deviation 18.82	5.2 Millimeters of mercury (mmHg) Standard Deviation 18.32
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 12 DAY 1; n=15, 13	2.7 Millimeters of mercury (mmHg) Standard Deviation 12.34	5.2 Millimeters of mercury (mmHg) Standard Deviation 14.73
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 13 DAY 1; n=13, 12	2.3 Millimeters of mercury (mmHg) Standard Deviation 12.26	3.0 Millimeters of mercury (mmHg) Standard Deviation 14.91
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 14 DAY 1; n=12, 12	-1.0 Millimeters of mercury (mmHg) Standard Deviation 10.13	4.0 Millimeters of mercury (mmHg) Standard Deviation 14.63
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 15 DAY 1; n=10, 9	1.4 Millimeters of mercury (mmHg) Standard Deviation 8.21	6.7 Millimeters of mercury (mmHg) Standard Deviation 21.05
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 16 DAY 1; n=10, 9	1.8 Millimeters of mercury (mmHg) Standard Deviation 5.79	7.9 Millimeters of mercury (mmHg) Standard Deviation 15.28
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 17 DAY 1; n=8, 8	1.3 Millimeters of mercury (mmHg) Standard Deviation 11.95	10.1 Millimeters of mercury (mmHg) Standard Deviation 17.70
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 18 DAY 1; n=8, 8	-2.0 Millimeters of mercury (mmHg) Standard Deviation 9.26	9.5 Millimeters of mercury (mmHg) Standard Deviation 19.41
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 19 DAY 1; n=6, 8	-4.8 Millimeters of mercury (mmHg) Standard Deviation 14.93	8.4 Millimeters of mercury (mmHg) Standard Deviation 20.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 20 DAY 1; n=6, 8	1.2 Millimeters of mercury (mmHg) Standard Deviation 9.13	5.8 Millimeters of mercury (mmHg) Standard Deviation 19.33
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 21 DAY 1; n=4, 8	2.5 Millimeters of mercury (mmHg) Standard Deviation 8.23	10.0 Millimeters of mercury (mmHg) Standard Deviation 21.23
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 22 DAY 1; n=4, 8	6.0 Millimeters of mercury (mmHg) Standard Deviation 10.55	5.5 Millimeters of mercury (mmHg) Standard Deviation 14.11
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 23 DAY 1; n=4, 8	-1.0 Millimeters of mercury (mmHg) Standard Deviation 10.80	12.9 Millimeters of mercury (mmHg) Standard Deviation 20.15
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 24 DAY 1; n=4, 8	-3.0 Millimeters of mercury (mmHg) Standard Deviation 6.38	5.6 Millimeters of mercury (mmHg) Standard Deviation 19.86
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 25 DAY 1; n=4, 8	1.3 Millimeters of mercury (mmHg) Standard Deviation 12.20	11.3 Millimeters of mercury (mmHg) Standard Deviation 20.08
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 26 DAY 1; n=4, 7	6.0 Millimeters of mercury (mmHg) Standard Deviation 11.89	9.3 Millimeters of mercury (mmHg) Standard Deviation 22.92
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 27 DAY 1; n=4, 5	3.3 Millimeters of mercury (mmHg) Standard Deviation 10.44	8.4 Millimeters of mercury (mmHg) Standard Deviation 18.04
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 28 DAY 1; n=4, 5	3.3 Millimeters of mercury (mmHg) Standard Deviation 7.41	5.2 Millimeters of mercury (mmHg) Standard Deviation 20.19
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 29 DAY 1; n=3, 4	-0.7 Millimeters of mercury (mmHg) Standard Deviation 14.29	3.3 Millimeters of mercury (mmHg) Standard Deviation 24.27
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 30 DAY 1; n=3, 4	2.7 Millimeters of mercury (mmHg) Standard Deviation 6.43	-2.3 Millimeters of mercury (mmHg) Standard Deviation 13.43
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 31 DAY 1; n=3, 4	-3.0 Millimeters of mercury (mmHg) Standard Deviation 11.79	2.0 Millimeters of mercury (mmHg) Standard Deviation 23.15
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 32 DAY 1; n=3, 4	5.0 Millimeters of mercury (mmHg) Standard Deviation 4.58	3.3 Millimeters of mercury (mmHg) Standard Deviation 16.40
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 33 DAY 1; n=2, 4	0.0 Millimeters of mercury (mmHg) Standard Deviation 14.14	-5.3 Millimeters of mercury (mmHg) Standard Deviation 19.96
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 34 DAY 1; n=1, 4	13.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	-5.3 Millimeters of mercury (mmHg) Standard Deviation 10.66
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 35 DAY 1; n=0, 4	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 15.81
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 36 DAY 1; n=0, 4	—	-1.5 Millimeters of mercury (mmHg) Standard Deviation 13.00
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 37 DAY 1; n=0, 3	—	-6.0 Millimeters of mercury (mmHg) Standard Deviation 23.52
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 38 DAY 1; n=0, 3	—	-1.3 Millimeters of mercury (mmHg) Standard Deviation 18.04
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 39 DAY 1; n=0, 3	—	-4.3 Millimeters of mercury (mmHg) Standard Deviation 21.01
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 40 DAY 1; n=0, 2	—	-12.5 Millimeters of mercury (mmHg) Standard Deviation 10.61
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 41 DAY 1; n=0, 2	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation 21.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 42 DAY 1; n=0, 2	—	-7.5 Millimeters of mercury (mmHg) Standard Deviation 17.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 43 DAY 1; n=0, 2	—	-17.5 Millimeters of mercury (mmHg) Standard Deviation 17.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 44 DAY 1; n=0, 2	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation 14.14
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 45 DAY 1; n=0, 2	—	-17.5 Millimeters of mercury (mmHg) Standard Deviation 17.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 46 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 21.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 47 DAY 1; n=0, 2	—	-17.5 Millimeters of mercury (mmHg) Standard Deviation 17.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 48 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 21.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 49 DAY 1; n=0, 2	—	-17.5 Millimeters of mercury (mmHg) Standard Deviation 17.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 50 DAY 1; n=0, 2	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation 21.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 51 DAY 1; n=0, 2	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation 21.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 52 DAY 1; n=0, 2	—	-17.5 Millimeters of mercury (mmHg) Standard Deviation 17.68
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 53 DAY 1; n=0, 2	—	-20.0 Millimeters of mercury (mmHg) Standard Deviation 14.14
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 54 DAY 1; n=0, 2	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation 14.14
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 55 DAY 1; n=0, 1	—	-30.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 56 DAY 1; n=0, 1	—	-30.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 57 DAY 1; n=0, 1	—	-30.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 58 DAY 1; n=0, 1	—	-25.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 59 DAY 1; n=0, 1	—	-20.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 60 DAY 1; n=0, 1	—	-30.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 61 DAY 1; n=0, 1	—	-25.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 62 DAY 1; n=0, 1	—	-23.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 63 DAY 1; n=0, 1	—	-28.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 64 DAY 1; n=0, 1	—	-25.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 65 DAY 1; n=0, 1	—	-26.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 66 DAY 1; n=0, 1	—	-32.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 67 DAY 1; n=0, 1	—	-33.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 68 DAY 1; n=0, 1	—	-32.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 69 DAY 1; n=0, 1	—	-31.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 70 DAY 1; n=0, 1	—	-25.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 71 DAY 1; n=0, 1	—	-28.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 72 DAY 1; n=0, 1	—	-30.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 73 DAY 1; n=0, 1	—	-27.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 74 DAY 1; n=0, 1	—	-30.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP; CYCLE 75 DAY 1; n=0, 1	—	-28.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; Cycle 2 Day 1, n=46, 44	-0.6 Millimeters of mercury (mmHg) Standard Deviation 8.51	0.7 Millimeters of mercury (mmHg) Standard Deviation 9.82
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 3 DAY 1, n=39, 35	2.1 Millimeters of mercury (mmHg) Standard Deviation 7.20	1.4 Millimeters of mercury (mmHg) Standard Deviation 8.90
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 4; DAY 1; n=33, 32	1.8 Millimeters of mercury (mmHg) Standard Deviation 10.52	2.4 Millimeters of mercury (mmHg) Standard Deviation 8.22
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 5 DAY 1; n=27, 26	0.9 Millimeters of mercury (mmHg) Standard Deviation 10.00	3.0 Millimeters of mercury (mmHg) Standard Deviation 15.49
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 6 DAY 1; n=24, 22	3.5 Millimeters of mercury (mmHg) Standard Deviation 8.32	1.2 Millimeters of mercury (mmHg) Standard Deviation 10.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 7 DAY 1; n=24, 22	0.5 Millimeters of mercury (mmHg) Standard Deviation 8.57	2.0 Millimeters of mercury (mmHg) Standard Deviation 7.42
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 8 DAY 1; n=22, 21	0.5 Millimeters of mercury (mmHg) Standard Deviation 7.37	2.3 Millimeters of mercury (mmHg) Standard Deviation 8.27
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 9 DAY 1; n=19, 16	2.7 Millimeters of mercury (mmHg) Standard Deviation 8.67	4.1 Millimeters of mercury (mmHg) Standard Deviation 9.15
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 10 DAY 1; n=18, 16	2.7 Millimeters of mercury (mmHg) Standard Deviation 9.81	2.4 Millimeters of mercury (mmHg) Standard Deviation 7.50
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 11 DAY 1; n=16, 15	-0.1 Millimeters of mercury (mmHg) Standard Deviation 10.25	0.9 Millimeters of mercury (mmHg) Standard Deviation 9.49
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 12 DAY 1; n=15, 13	0.6 Millimeters of mercury (mmHg) Standard Deviation 7.80	2.1 Millimeters of mercury (mmHg) Standard Deviation 8.65
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 13 DAY 1; n=13, 12	-2.2 Millimeters of mercury (mmHg) Standard Deviation 6.07	-2.7 Millimeters of mercury (mmHg) Standard Deviation 7.64
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 14 DAY 1; n=12, 12	0.7 Millimeters of mercury (mmHg) Standard Deviation 6.87	3.3 Millimeters of mercury (mmHg) Standard Deviation 11.78
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 15 DAY 1; n=10, 9	2.1 Millimeters of mercury (mmHg) Standard Deviation 8.49	1.1 Millimeters of mercury (mmHg) Standard Deviation 12.97
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 16 DAY 1; n=10, 9	0.1 Millimeters of mercury (mmHg) Standard Deviation 7.68	0.1 Millimeters of mercury (mmHg) Standard Deviation 11.88
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 17 DAY 1; n=8, 8	-1.5 Millimeters of mercury (mmHg) Standard Deviation 8.23	5.0 Millimeters of mercury (mmHg) Standard Deviation 7.15
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 18 DAY 1; n=8, 8	0.1 Millimeters of mercury (mmHg) Standard Deviation 6.47	3.4 Millimeters of mercury (mmHg) Standard Deviation 11.15
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 19 DAY 1; n=6, 8	-2.5 Millimeters of mercury (mmHg) Standard Deviation 5.82	5.5 Millimeters of mercury (mmHg) Standard Deviation 12.17
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 20 DAY 1; n=6, 8	2.3 Millimeters of mercury (mmHg) Standard Deviation 3.83	3.5 Millimeters of mercury (mmHg) Standard Deviation 10.09
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 21 DAY 1; n=4, 8	0.8 Millimeters of mercury (mmHg) Standard Deviation 2.99	2.8 Millimeters of mercury (mmHg) Standard Deviation 11.96
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 22 DAY 1; n=4, 8	-1.8 Millimeters of mercury (mmHg) Standard Deviation 3.95	3.8 Millimeters of mercury (mmHg) Standard Deviation 7.63
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 23 DAY 1; n=4, 8	2.5 Millimeters of mercury (mmHg) Standard Deviation 4.20	5.1 Millimeters of mercury (mmHg) Standard Deviation 12.12
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 24 DAY 1; n=4, 8	-3.0 Millimeters of mercury (mmHg) Standard Deviation 11.17	2.5 Millimeters of mercury (mmHg) Standard Deviation 12.99
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 25 DAY 1; n=4, 8	3.5 Millimeters of mercury (mmHg) Standard Deviation 3.11	2.5 Millimeters of mercury (mmHg) Standard Deviation 15.80
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 26 DAY 1; n=4, 7	0.0 Millimeters of mercury (mmHg) Standard Deviation 3.27	4.0 Millimeters of mercury (mmHg) Standard Deviation 14.57
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 27 DAY 1; n=4, 5	-3.3 Millimeters of mercury (mmHg) Standard Deviation 4.72	3.6 Millimeters of mercury (mmHg) Standard Deviation 11.67
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 28 DAY 1; n=4, 5	2.0 Millimeters of mercury (mmHg) Standard Deviation 1.63	4.0 Millimeters of mercury (mmHg) Standard Deviation 14.21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 29 DAY 1; n=3, 4	1.7 Millimeters of mercury (mmHg) Standard Deviation 10.41	-2.0 Millimeters of mercury (mmHg) Standard Deviation 7.26
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 30 DAY 1; n=3, 4	-0.3 Millimeters of mercury (mmHg) Standard Deviation 4.04	-2.3 Millimeters of mercury (mmHg) Standard Deviation 6.60
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 31 DAY 1; n=3, 4	6.7 Millimeters of mercury (mmHg) Standard Deviation 7.64	0.5 Millimeters of mercury (mmHg) Standard Deviation 11.45
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 32 DAY 1; n=3, 4	2.7 Millimeters of mercury (mmHg) Standard Deviation 7.51	-0.3 Millimeters of mercury (mmHg) Standard Deviation 7.76
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 33 DAY 1; n=2, 4	0.5 Millimeters of mercury (mmHg) Standard Deviation 7.78	-2.5 Millimeters of mercury (mmHg) Standard Deviation 8.50
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 34 DAY 1; n=1, 4	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	-1.8 Millimeters of mercury (mmHg) Standard Deviation 6.99
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 35 DAY 1; n=0, 4	—	-3.0 Millimeters of mercury (mmHg) Standard Deviation 8.12
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 36 DAY 1; n=0, 4	—	1.5 Millimeters of mercury (mmHg) Standard Deviation 3.00
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 37 DAY 1; n=0, 3	—	1.7 Millimeters of mercury (mmHg) Standard Deviation 12.58
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 38 DAY 1; n=0, 3	—	-2.3 Millimeters of mercury (mmHg) Standard Deviation 6.81
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 39 DAY 1; n=0, 3	—	0.3 Millimeters of mercury (mmHg) Standard Deviation 10.50
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 40 DAY 1; n=0, 2	—	0.0 Millimeters of mercury (mmHg) Standard Deviation 0.00
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 41 DAY 1; n=0, 2	—	-7.5 Millimeters of mercury (mmHg) Standard Deviation 3.54
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 42 DAY 1; n=0, 2	—	0.0 Millimeters of mercury (mmHg) Standard Deviation 0.00
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 43 DAY 1; n=0, 2	—	-7.5 Millimeters of mercury (mmHg) Standard Deviation 3.54
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 44 DAY 1; n=0, 2	—	-2.5 Millimeters of mercury (mmHg) Standard Deviation 3.54
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 45 DAY 1; n=0, 2	—	-7.5 Millimeters of mercury (mmHg) Standard Deviation 3.54
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 46 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 7.07
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 47 DAY 1; n=0, 2	—	-3.0 Millimeters of mercury (mmHg) Standard Deviation 24.04
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 48 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 7.07
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 49 DAY 1; n=0, 2	—	-12.5 Millimeters of mercury (mmHg) Standard Deviation 3.54
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 50 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 7.07
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 51 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 7.07
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 52 DAY 1; n=0, 2	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation 7.07
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 53 DAY 1; n=0, 2	—	-7.5 Millimeters of mercury (mmHg) Standard Deviation 3.54
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 54 DAY 1; n=0, 2	—	-5.0 Millimeters of mercury (mmHg) Standard Deviation 7.07
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 55 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 56 DAY 1; n=0, 1	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 57 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 58 DAY 1; n=0, 1	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 59 DAY 1; n=0, 1	—	-10.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 60 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 61 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 62 DAY 1; n=0, 1	—	-13.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 63 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 64 DAY 1; n=0, 1	—	-14.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 65 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 66 DAY 1; n=0, 1	—	-17.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 67 DAY 1; n=0, 1	—	-14.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 68 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 69 DAY 1; n=0, 1	—	-17.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 70 DAY 1; n=0, 1	—	-16.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 71 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 72 DAY 1; n=0, 1	—	-19.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 73 DAY 1; n=0, 1	—	-15.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 74 DAY 1; n=0, 1	—	-14.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP; CYCLE 75 DAY 1; n=0, 1	—	-17.0 Millimeters of mercury (mmHg) Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.

SECONDARY outcome

Timeframe: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)

Population: As Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Heart rate was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Change From Baseline in Heart Rate CYCLE 51 DAY 1; n=0, 2	—	-5.0 Beats per minute Standard Deviation 12.73
Change From Baseline in Heart Rate CYCLE 52 DAY 1; n=0, 2	—	-8.0 Beats per minute Standard Deviation 11.31
Change From Baseline in Heart Rate CYCLE 53 DAY 1; n=0, 2	—	-10.0 Beats per minute Standard Deviation 2.83
Change From Baseline in Heart Rate CYCLE 54 DAY 1; n=0, 2	—	-2.0 Beats per minute Standard Deviation 8.49
Change From Baseline in Heart Rate CYCLE 55 DAY 1; n=0, 1	—	-10.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 56 DAY 1; n=0, 1	—	-12.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate Cycle 2 Day 1, n=46, 44	0.7 Beats per minute Standard Deviation 8.32	-1.8 Beats per minute Standard Deviation 9.42
Change From Baseline in Heart Rate CYCLE 3 DAY 1, n=39, 35	1.7 Beats per minute Standard Deviation 7.69	-1.6 Beats per minute Standard Deviation 6.78
Change From Baseline in Heart Rate CYCLE 4; DAY 1; n=33, 32	1.0 Beats per minute Standard Deviation 10.09	1.9 Beats per minute Standard Deviation 7.61
Change From Baseline in Heart Rate CYCLE 5 DAY 1; n=27, 26	1.3 Beats per minute Standard Deviation 9.45	0.2 Beats per minute Standard Deviation 10.65
Change From Baseline in Heart Rate CYCLE 6 DAY 1; n=24, 22	0.2 Beats per minute Standard Deviation 10.37	0.3 Beats per minute Standard Deviation 8.31
Change From Baseline in Heart Rate CYCLE 7 DAY 1; n=24, 22	2.0 Beats per minute Standard Deviation 8.40	-1.8 Beats per minute Standard Deviation 8.80
Change From Baseline in Heart Rate CYCLE 57 DAY 1; n=0, 1	—	-10.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 8 DAY 1; n=22, 21	0.5 Beats per minute Standard Deviation 7.70	-0.4 Beats per minute Standard Deviation 7.30
Change From Baseline in Heart Rate CYCLE 9 DAY 1; n=19, 16	2.1 Beats per minute Standard Deviation 8.04	0.3 Beats per minute Standard Deviation 7.10
Change From Baseline in Heart Rate CYCLE 10 DAY 1; n=18, 16	2.3 Beats per minute Standard Deviation 8.62	0.5 Beats per minute Standard Deviation 13.54
Change From Baseline in Heart Rate CYCLE 11 DAY 1; n=16, 15	-0.8 Beats per minute Standard Deviation 6.51	-2.0 Beats per minute Standard Deviation 9.88
Change From Baseline in Heart Rate CYCLE 12 DAY 1; n=15, 13	-0.7 Beats per minute Standard Deviation 4.28	0.2 Beats per minute Standard Deviation 9.92
Change From Baseline in Heart Rate CYCLE 13 DAY 1; n=13, 12	0.9 Beats per minute Standard Deviation 5.47	0.9 Beats per minute Standard Deviation 9.77
Change From Baseline in Heart Rate CYCLE 14 DAY 1; n=12, 12	1.6 Beats per minute Standard Deviation 7.03	3.1 Beats per minute Standard Deviation 10.25
Change From Baseline in Heart Rate CYCLE 15 DAY 1; n=10, 9	5.6 Beats per minute Standard Deviation 12.39	2.2 Beats per minute Standard Deviation 8.51
Change From Baseline in Heart Rate CYCLE 16 DAY 1; n=10, 9	3.3 Beats per minute Standard Deviation 7.06	0.7 Beats per minute Standard Deviation 9.12
Change From Baseline in Heart Rate CYCLE 17 DAY 1; n=8, 8	3.1 Beats per minute Standard Deviation 7.20	1.6 Beats per minute Standard Deviation 10.23
Change From Baseline in Heart Rate CYCLE 18 DAY 1; n=8, 8	6.4 Beats per minute Standard Deviation 8.68	-0.5 Beats per minute Standard Deviation 6.12
Change From Baseline in Heart Rate CYCLE 19 DAY 1; n=6, 8	-2.5 Beats per minute Standard Deviation 10.54	0.5 Beats per minute Standard Deviation 9.78
Change From Baseline in Heart Rate CYCLE 20 DAY 1; n=6, 8	0.3 Beats per minute Standard Deviation 6.38	0.9 Beats per minute Standard Deviation 7.36
Change From Baseline in Heart Rate CYCLE 21 DAY 1; n=4, 8	0.5 Beats per minute Standard Deviation 1.91	-1.4 Beats per minute Standard Deviation 10.28
Change From Baseline in Heart Rate CYCLE 22 DAY 1; n=4, 8	0.5 Beats per minute Standard Deviation 1.91	3.0 Beats per minute Standard Deviation 13.41
Change From Baseline in Heart Rate CYCLE 23 DAY 1; n=4, 8	-3.8 Beats per minute Standard Deviation 6.02	2.9 Beats per minute Standard Deviation 9.76
Change From Baseline in Heart Rate CYCLE 24 DAY 1; n=4, 8	-2.5 Beats per minute Standard Deviation 5.97	2.9 Beats per minute Standard Deviation 10.92
Change From Baseline in Heart Rate CYCLE 25 DAY 1; n=4, 8	-1.8 Beats per minute Standard Deviation 2.06	0.3 Beats per minute Standard Deviation 11.13
Change From Baseline in Heart Rate CYCLE 26 DAY 1; n=4, 7	-0.5 Beats per minute Standard Deviation 1.91	1.6 Beats per minute Standard Deviation 11.43
Change From Baseline in Heart Rate CYCLE 27 DAY 1; n=4, 5	-2.0 Beats per minute Standard Deviation 2.31	2.4 Beats per minute Standard Deviation 11.70
Change From Baseline in Heart Rate CYCLE 28 DAY 1; n=4, 5	-1.8 Beats per minute Standard Deviation 5.56	-0.2 Beats per minute Standard Deviation 13.68
Change From Baseline in Heart Rate CYCLE 29 DAY 1; n=3, 4	0.0 Beats per minute Standard Deviation 4.00	-3.8 Beats per minute Standard Deviation 6.45
Change From Baseline in Heart Rate CYCLE 30 DAY 1; n=3, 4	0.3 Beats per minute Standard Deviation 2.08	-9.3 Beats per minute Standard Deviation 5.25
Change From Baseline in Heart Rate CYCLE 31 DAY 1; n=3, 4	-2.7 Beats per minute Standard Deviation 6.43	-0.8 Beats per minute Standard Deviation 8.77
Change From Baseline in Heart Rate CYCLE 32 DAY 1; n=3, 4	2.0 Beats per minute Standard Deviation 4.00	-3.8 Beats per minute Standard Deviation 6.65
Change From Baseline in Heart Rate CYCLE 33 DAY 1; n=2, 4	-2.0 Beats per minute Standard Deviation 0.00	-5.5 Beats per minute Standard Deviation 7.55
Change From Baseline in Heart Rate CYCLE 34 DAY 1; n=1, 4	0.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	-3.5 Beats per minute Standard Deviation 4.43
Change From Baseline in Heart Rate CYCLE 35 DAY 1; n=0, 4	—	-4.8 Beats per minute Standard Deviation 4.99
Change From Baseline in Heart Rate CYCLE 36 DAY 1; n=0, 4	—	-8.0 Beats per minute Standard Deviation 8.37
Change From Baseline in Heart Rate CYCLE 37 DAY 1; n=0, 3	—	-9.3 Beats per minute Standard Deviation 6.11
Change From Baseline in Heart Rate CYCLE 38 DAY 1; n=0, 3	—	-2.0 Beats per minute Standard Deviation 6.93
Change From Baseline in Heart Rate CYCLE 39 DAY 1; n=0, 3	—	-4.7 Beats per minute Standard Deviation 6.43
Change From Baseline in Heart Rate CYCLE 40 DAY 1; n=0, 2	—	-4.0 Beats per minute Standard Deviation 8.49
Change From Baseline in Heart Rate CYCLE 41 DAY 1; n=0, 2	—	-7.0 Beats per minute Standard Deviation 9.90
Change From Baseline in Heart Rate CYCLE 42 DAY 1; n=0, 2	—	-2.0 Beats per minute Standard Deviation 8.49
Change From Baseline in Heart Rate CYCLE 43 DAY 1; n=0, 2	—	-6.0 Beats per minute Standard Deviation 14.14
Change From Baseline in Heart Rate CYCLE 44 DAY 1; n=0, 2	—	-2.0 Beats per minute Standard Deviation 14.14
Change From Baseline in Heart Rate CYCLE 45 DAY 1; n=0, 2	—	-4.0 Beats per minute Standard Deviation 14.14
Change From Baseline in Heart Rate CYCLE 46 DAY 1; n=0, 2	—	-3.0 Beats per minute Standard Deviation 18.38
Change From Baseline in Heart Rate CYCLE 47 DAY 1; n=0, 2	—	-2.0 Beats per minute Standard Deviation 14.14
Change From Baseline in Heart Rate CYCLE 48 DAY 1; n=0, 2	—	-3.0 Beats per minute Standard Deviation 15.56
Change From Baseline in Heart Rate CYCLE 49 DAY 1; n=0, 2	—	-9.0 Beats per minute Standard Deviation 9.90
Change From Baseline in Heart Rate CYCLE 50 DAY 1; n=0, 2	—	-5.0 Beats per minute Standard Deviation 9.90
Change From Baseline in Heart Rate CYCLE 58 DAY 1; n=0, 1	—	-8.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 59 DAY 1; n=0, 1	—	-12.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 60 DAY 1; n=0, 1	—	-10.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 61 DAY 1; n=0, 1	—	-12.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 62 DAY 1; n=0, 1	—	-14.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 63 DAY 1; n=0, 1	—	-15.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 64 DAY 1; n=0, 1	—	-10.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 65 DAY 1; n=0, 1	—	-11.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 66 DAY 1; n=0, 1	—	-12.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 67 DAY 1; n=0, 1	—	-9.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 68 DAY 1; n=0, 1	—	-10.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 69 DAY 1; n=0, 1	—	-12.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 70 DAY 1; n=0, 1	—	-9.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 71 DAY 1; n=0, 1	—	-7.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 72 DAY 1; n=0, 1	—	-10.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 73 DAY 1; n=0, 1	—	-9.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 74 DAY 1; n=0, 1	—	-8.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Heart Rate CYCLE 75 DAY 1; n=0, 1	—	-9.0 Beats per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.

SECONDARY outcome

Timeframe: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)

Population: As Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Temperature was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Change From Baseline in Temperature Cycle 2 Day 1, n=46, 43	0.02 Celsius Standard Deviation 0.288	-0.02 Celsius Standard Deviation 0.242
Change From Baseline in Temperature CYCLE 3 DAY 1, n=39, 35	-0.01 Celsius Standard Deviation 0.374	-0.11 Celsius Standard Deviation 0.340
Change From Baseline in Temperature CYCLE 4; DAY 1; n=33, 32	0.02 Celsius Standard Deviation 0.354	-0.05 Celsius Standard Deviation 0.298
Change From Baseline in Temperature CYCLE 5 DAY 1; n=27, 26	0.05 Celsius Standard Deviation 0.374	-0.04 Celsius Standard Deviation 0.218
Change From Baseline in Temperature CYCLE 6 DAY 1; n=23, 22	-0.05 Celsius Standard Deviation 0.374	-0.07 Celsius Standard Deviation 0.223
Change From Baseline in Temperature CYCLE 7 DAY 1; n=24, 22	0.03 Celsius Standard Deviation 0.334	-0.10 Celsius Standard Deviation 0.408
Change From Baseline in Temperature CYCLE 8 DAY 1; n=21, 21	0.01 Celsius Standard Deviation 0.460	0.02 Celsius Standard Deviation 0.161
Change From Baseline in Temperature CYCLE 9 DAY 1; n=19, 16	0.04 Celsius Standard Deviation 0.493	0.00 Celsius Standard Deviation 0.171
Change From Baseline in Temperature CYCLE 10 DAY 1; n=18, 16	0.05 Celsius Standard Deviation 0.539	0.04 Celsius Standard Deviation 0.200
Change From Baseline in Temperature CYCLE 11 DAY 1; n=16, 15	-0.02 Celsius Standard Deviation 0.468	-0.09 Celsius Standard Deviation 0.181
Change From Baseline in Temperature CYCLE 12 DAY 1; n=15, 13	0.00 Celsius Standard Deviation 0.270	0.02 Celsius Standard Deviation 0.245
Change From Baseline in Temperature CYCLE 13 DAY 1; n=13, 12	0.00 Celsius Standard Deviation 0.354	0.03 Celsius Standard Deviation 0.176
Change From Baseline in Temperature CYCLE 14 DAY 1; n=12, 12	0.13 Celsius Standard Deviation 0.380	-0.04 Celsius Standard Deviation 0.219
Change From Baseline in Temperature CYCLE 15 DAY 1; n=10, 9	0.11 Celsius Standard Deviation 0.420	-0.13 Celsius Standard Deviation 0.269
Change From Baseline in Temperature CYCLE 16 DAY 1; n=10, 9	0.01 Celsius Standard Deviation 0.318	-0.04 Celsius Standard Deviation 0.174
Change From Baseline in Temperature CYCLE 17 DAY 1; n=8, 8	0.00 Celsius Standard Deviation 0.227	0.05 Celsius Standard Deviation 0.076
Change From Baseline in Temperature CYCLE 18 DAY 1; n=8, 8	-0.14 Celsius Standard Deviation 0.346	-0.09 Celsius Standard Deviation 0.189
Change From Baseline in Temperature CYCLE 19 DAY 1; n=6, 8	-0.10 Celsius Standard Deviation 0.456	0.10 Celsius Standard Deviation 0.207
Change From Baseline in Temperature CYCLE 20 DAY 1; n=6, 8	-0.02 Celsius Standard Deviation 0.397	0.01 Celsius Standard Deviation 0.146
Change From Baseline in Temperature CYCLE 21 DAY 1; n=4, 8	0.13 Celsius Standard Deviation 0.411	-0.01 Celsius Standard Deviation 0.304
Change From Baseline in Temperature CYCLE 22 DAY 1; n=4, 8	0.17 Celsius Standard Deviation 0.206	0.00 Celsius Standard Deviation 0.193
Change From Baseline in Temperature CYCLE 23 DAY 1; n=4, 8	0.03 Celsius Standard Deviation 0.299	0.13 Celsius Standard Deviation 0.231
Change From Baseline in Temperature CYCLE 24 DAY 1; n=4, 8	0.18 Celsius Standard Deviation 0.171	0.06 Celsius Standard Deviation 0.119
Change From Baseline in Temperature CYCLE 25 DAY 1; n=4, 8	0.20 Celsius Standard Deviation 0.432	0.00 Celsius Standard Deviation 0.185
Change From Baseline in Temperature CYCLE 26 DAY 1; n=4, 7	0.15 Celsius Standard Deviation 0.129	-0.01 Celsius Standard Deviation 0.308
Change From Baseline in Temperature CYCLE 27 DAY 1; n=4, 5	0.18 Celsius Standard Deviation 0.171	0.10 Celsius Standard Deviation 0.173
Change From Baseline in Temperature CYCLE 28 DAY 1; n=4, 5	0.15 Celsius Standard Deviation 0.208	-0.02 Celsius Standard Deviation 0.179
Change From Baseline in Temperature CYCLE 29 DAY 1; n=3, 4	0.13 Celsius Standard Deviation 0.153	-0.02 Celsius Standard Deviation 0.275
Change From Baseline in Temperature CYCLE 30 DAY 1; n=3, 4	0.10 Celsius Standard Deviation 0.173	0.00 Celsius Standard Deviation 0.082
Change From Baseline in Temperature CYCLE 31 DAY 1; n=3, 4	-0.07 Celsius Standard Deviation 0.351	0.05 Celsius Standard Deviation 0.265
Change From Baseline in Temperature CYCLE 32 DAY 1; n=3, 4	0.10 Celsius Standard Deviation 0.173	-0.05 Celsius Standard Deviation 0.265
Change From Baseline in Temperature CYCLE 33 DAY 1; n=2, 4	0.30 Celsius Standard Deviation 0.424	-0.07 Celsius Standard Deviation 0.222
Change From Baseline in Temperature CYCLE 34 DAY 1; n=1, 4	0.30 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point	-0.20 Celsius Standard Deviation 0.283
Change From Baseline in Temperature CYCLE 35 DAY 1; n=0, 4	—	-0.05 Celsius Standard Deviation 0.058
Change From Baseline in Temperature CYCLE 36 DAY 1; n=0, 4	—	-0.07 Celsius Standard Deviation 0.150
Change From Baseline in Temperature CYCLE 37 DAY 1; n=0, 3	—	-0.30 Celsius Standard Deviation 0.458
Change From Baseline in Temperature CYCLE 38 DAY 1; n=0, 3	—	0.00 Celsius Standard Deviation 0.100
Change From Baseline in Temperature CYCLE 39 DAY 1; n=0, 3	—	-0.07 Celsius Standard Deviation 0.058
Change From Baseline in Temperature CYCLE 40 DAY 1; n=0, 2	—	0.00 Celsius Standard Deviation 0.00
Change From Baseline in Temperature CYCLE 41 DAY 1; n=0, 2	—	-0.10 Celsius Standard Deviation 0.141
Change From Baseline in Temperature CYCLE 42 DAY 1; n=0, 2	—	0.05 Celsius Standard Deviation 0.071
Change From Baseline in Temperature CYCLE 43 DAY 1; n=0, 2	—	-0.05 Celsius Standard Deviation 0.212
Change From Baseline in Temperature CYCLE 44 DAY 1; n=0, 2	—	0.00 Celsius Standard Deviation 0.141
Change From Baseline in Temperature CYCLE 45 DAY 1; n=0, 2	—	0.00 Celsius Standard Deviation 0.283
Change From Baseline in Temperature CYCLE 46 DAY 1; n=0, 2	—	-0.05 Celsius Standard Deviation 0.071
Change From Baseline in Temperature CYCLE 47 DAY 1; n=0, 2	—	0.05 Celsius Standard Deviation 0.212
Change From Baseline in Temperature CYCLE 48 DAY 1; n=0, 2	—	0.00 Celsius Standard Deviation 0.000
Change From Baseline in Temperature CYCLE 49 DAY 1; n=0, 2	—	-0.05 Celsius Standard Deviation 0.212
Change From Baseline in Temperature CYCLE 50 DAY 1; n=0, 2	—	0.00 Celsius Standard Deviation 0.141
Change From Baseline in Temperature CYCLE 51 DAY 1; n=0, 2	—	-0.05 Celsius Standard Deviation 0.071
Change From Baseline in Temperature CYCLE 52 DAY 1; n=0, 2	—	-0.10 Celsius Standard Deviation 0.141
Change From Baseline in Temperature CYCLE 53 DAY 1; n=0, 2	—	0.05 Celsius Standard Deviation 0.071
Change From Baseline in Temperature CYCLE 54 DAY 1; n=0, 2	—	-0.05 Celsius Standard Deviation 0.071
Change From Baseline in Temperature CYCLE 55 DAY 1; n=0, 1	—	-0.20 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 56 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 57 DAY 1; n=0, 1	—	0.00 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 58 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 59 DAY 1; n=0, 1	—	0.00 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 60 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 61 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 62 DAY 1; n=0, 1	—	0.00 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 63 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 64 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 65 DAY 1; n=0, 1	—	0.00 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 66 DAY 1; n=0, 1	—	-0.20 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 67 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 68 DAY 1; n=0, 1	—	0.00 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 69 DAY 1; n=0, 1	—	-0.20 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 70 DAY 1; n=0, 1	—	0.00 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 71 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 72 DAY 1; n=0, 1	—	-0.20 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 73 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 74 DAY 1; n=0, 1	—	-0.20 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point
Change From Baseline in Temperature CYCLE 75 DAY 1; n=0, 1	—	-0.10 Celsius Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point

SECONDARY outcome

Timeframe: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)

Population: As Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Respiratory rate was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose.Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Change From Baseline in Respiratory Rate CYCLE 29 DAY 1; n=3, 4	-0.7 Breaths per minute Standard Deviation 1.53	-0.3 Breaths per minute Standard Deviation 2.22
Change From Baseline in Respiratory Rate CYCLE 65 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 2 Day 1, n=46, 44	-0.1 Breaths per minute Standard Deviation 1.62	0.1 Breaths per minute Standard Deviation 1.31
Change From Baseline in Respiratory Rate CYCLE 3 DAY 1, n=39, 35	0.2 Breaths per minute Standard Deviation 2.34	-0.2 Breaths per minute Standard Deviation 1.71
Change From Baseline in Respiratory Rate CYCLE 4; DAY 1; n=32, 32	0.2 Breaths per minute Standard Deviation 1.79	-0.3 Breaths per minute Standard Deviation 1.45
Change From Baseline in Respiratory Rate CYCLE 5 DAY 1; n=26, 26	-0.1 Breaths per minute Standard Deviation 1.86	-0.3 Breaths per minute Standard Deviation 1.50
Change From Baseline in Respiratory Rate CYCLE 6 DAY 1; n=24, 22	0.5 Breaths per minute Standard Deviation 2.15	-0.3 Breaths per minute Standard Deviation 1.88
Change From Baseline in Respiratory Rate CYCLE 7 DAY 1; n=24, 22	-0.1 Breaths per minute Standard Deviation 2.09	-0.2 Breaths per minute Standard Deviation 1.74
Change From Baseline in Respiratory Rate CYCLE 8 DAY 1; n=21, 21	0.6 Breaths per minute Standard Deviation 1.78	-0.1 Breaths per minute Standard Deviation 1.59
Change From Baseline in Respiratory Rate CYCLE 9 DAY 1; n=19, 16	-0.5 Breaths per minute Standard Deviation 1.98	-0.2 Breaths per minute Standard Deviation 2.04
Change From Baseline in Respiratory Rate CYCLE 10 DAY 1; n=18, 16	-1.7 Breaths per minute Standard Deviation 2.95	-0.4 Breaths per minute Standard Deviation 2.03
Change From Baseline in Respiratory Rate CYCLE 11 DAY 1; n=16, 15	-0.8 Breaths per minute Standard Deviation 1.97	-0.8 Breaths per minute Standard Deviation 2.21
Change From Baseline in Respiratory Rate CYCLE 12 DAY 1; n=15, 13	0.0 Breaths per minute Standard Deviation 2.48	-1.0 Breaths per minute Standard Deviation 2.45
Change From Baseline in Respiratory Rate CYCLE 13 DAY 1; n=13, 12	-0.2 Breaths per minute Standard Deviation 1.69	-0.7 Breaths per minute Standard Deviation 2.67
Change From Baseline in Respiratory Rate CYCLE 14 DAY 1; n=12, 12	0.4 Breaths per minute Standard Deviation 2.43	-1.0 Breaths per minute Standard Deviation 2.52
Change From Baseline in Respiratory Rate CYCLE 15 DAY 1; n=10, 9	-0.5 Breaths per minute Standard Deviation 1.65	-0.9 Breaths per minute Standard Deviation 3.06
Change From Baseline in Respiratory Rate CYCLE 16 DAY 1; n=10, 9	-0.5 Breaths per minute Standard Deviation 1.72	-0.9 Breaths per minute Standard Deviation 2.76
Change From Baseline in Respiratory Rate CYCLE 17 DAY 1; n=8, 8	0.0 Breaths per minute Standard Deviation 2.20	0.1 Breaths per minute Standard Deviation 1.81
Change From Baseline in Respiratory Rate CYCLE 18 DAY 1; n=8, 8	-0.4 Breaths per minute Standard Deviation 2.07	0.4 Breaths per minute Standard Deviation 1.60
Change From Baseline in Respiratory Rate CYCLE 19 DAY 1; n=6, 8	0.7 Breaths per minute Standard Deviation 1.37	0.0 Breaths per minute Standard Deviation 1.51
Change From Baseline in Respiratory Rate CYCLE 20 DAY 1; n=6, 8	0.2 Breaths per minute Standard Deviation 0.75	0.0 Breaths per minute Standard Deviation 1.60
Change From Baseline in Respiratory Rate CYCLE 21 DAY 1; n=4, 8	0.8 Breaths per minute Standard Deviation 0.96	-0.1 Breaths per minute Standard Deviation 1.64
Change From Baseline in Respiratory Rate CYCLE 22 DAY 1; n=4, 8	0.0 Breaths per minute Standard Deviation 0.00	-0.1 Breaths per minute Standard Deviation 1.36
Change From Baseline in Respiratory Rate CYCLE 23 DAY 1; n=4, 8	0.5 Breaths per minute Standard Deviation 1.00	0.4 Breaths per minute Standard Deviation 1.60
Change From Baseline in Respiratory Rate CYCLE 24 DAY 1; n=4, 8	-0.3 Breaths per minute Standard Deviation 1.26	0.0 Breaths per minute Standard Deviation 1.20
Change From Baseline in Respiratory Rate CYCLE 25 DAY 1; n=4, 8	-0.3 Breaths per minute Standard Deviation 0.50	-0.3 Breaths per minute Standard Deviation 1.49
Change From Baseline in Respiratory Rate CYCLE 26 DAY 1; n=4, 7	-0.5 Breaths per minute Standard Deviation 1.00	0.0 Breaths per minute Standard Deviation 1.63
Change From Baseline in Respiratory Rate CYCLE 27 DAY 1; n=4, 5	0.0 Breaths per minute Standard Deviation 1.41	0.0 Breaths per minute Standard Deviation 1.00
Change From Baseline in Respiratory Rate CYCLE 28 DAY 1; n=4, 5	-0.3 Breaths per minute Standard Deviation 0.50	0.2 Breaths per minute Standard Deviation 2.17
Change From Baseline in Respiratory Rate CYCLE 30 DAY 1; n=3, 4	0.0 Breaths per minute Standard Deviation 0.00	-0.3 Breaths per minute Standard Deviation 2.06
Change From Baseline in Respiratory Rate CYCLE 31 DAY 1; n=3, 4	0.7 Breaths per minute Standard Deviation 0.58	0.3 Breaths per minute Standard Deviation 2.36
Change From Baseline in Respiratory Rate CYCLE 32 DAY 1; n=3, 4	-0.7 Breaths per minute Standard Deviation 1.53	0.0 Breaths per minute Standard Deviation 2.16
Change From Baseline in Respiratory Rate CYCLE 33 DAY 1; n=2, 4	-2.0 Breaths per minute Standard Deviation 0.00	-0.8 Breaths per minute Standard Deviation 1.50
Change From Baseline in Respiratory Rate CYCLE 34 DAY 1; n=1, 4	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	0.8 Breaths per minute Standard Deviation 1.50
Change From Baseline in Respiratory Rate CYCLE 35 DAY 1; n=0, 4	—	0.0 Breaths per minute Standard Deviation 1.83
Change From Baseline in Respiratory Rate CYCLE 36 DAY 1; n=0, 4	—	0.3 Breaths per minute Standard Deviation 1.71
Change From Baseline in Respiratory Rate CYCLE 37 DAY 1; n=0, 3	—	-1.0 Breaths per minute Standard Deviation 1.73
Change From Baseline in Respiratory Rate CYCLE 38 DAY 1; n=0, 3	—	-0.3 Breaths per minute Standard Deviation 2.52
Change From Baseline in Respiratory Rate CYCLE 39 DAY 1; n=0, 3	—	-1.0 Breaths per minute Standard Deviation 1.73
Change From Baseline in Respiratory Rate CYCLE 40 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 41 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 42 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 43 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 44 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 45 DAY 1; n=0, 2	—	-1.5 Breaths per minute Standard Deviation 0.71
Change From Baseline in Respiratory Rate CYCLE 46 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 47 DAY 1; n=0, 2	—	-0.5 Breaths per minute Standard Deviation 0.71
Change From Baseline in Respiratory Rate CYCLE 48 DAY 1; n=0, 2	—	1.0 Breaths per minute Standard Deviation 1.41
Change From Baseline in Respiratory Rate CYCLE 49 DAY 1; n=0, 2	—	-1.0 Breaths per minute Standard Deviation 1.41
Change From Baseline in Respiratory Rate CYCLE 50 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 51 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 52 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 53 DAY 1; n=0, 2	—	-1.0 Breaths per minute Standard Deviation 1.41
Change From Baseline in Respiratory Rate CYCLE 54 DAY 1; n=0, 2	—	0.0 Breaths per minute Standard Deviation 0.00
Change From Baseline in Respiratory Rate CYCLE 55 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 56 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 57 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 58 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 59 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 60 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 61 DAY 1; n=0, 1	—	0.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 62 DAY 1; n=0, 1	—	-1.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 63 DAY 1; n=0, 1	—	-1.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 64 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 66 DAY 1; n=0, 1	—	-1.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 67 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 68 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 69 DAY 1; n=0, 1	—	-1.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 70 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 71 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 72 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 73 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 74 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Respiratory Rate CYCLE 75 DAY 1; n=0, 1	—	-2.0 Breaths per minute Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.

SECONDARY outcome

Timeframe: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)

Population: As Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).

Weight was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=51 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg n=50 Participants Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Change From Baseline in Weight CYCLE 21 DAY 1; n=4, 8	-3.03 Kilograms Standard Deviation 7.950	-0.29 Kilograms Standard Deviation 6.354
Change From Baseline in Weight Cycle 2 Day 1, n=46, 44	-1.51 Kilograms Standard Deviation 2.192	-1.55 Kilograms Standard Deviation 2.405
Change From Baseline in Weight CYCLE 3 DAY 1, n=39, 35	-2.54 Kilograms Standard Deviation 2.734	-1.88 Kilograms Standard Deviation 2.710
Change From Baseline in Weight CYCLE 4; DAY 1; n=33, 32	-3.02 Kilograms Standard Deviation 2.451	-1.86 Kilograms Standard Deviation 3.305
Change From Baseline in Weight CYCLE 5 DAY 1; n=27, 26	-3.31 Kilograms Standard Deviation 2.521	-2.01 Kilograms Standard Deviation 3.301
Change From Baseline in Weight CYCLE 6 DAY 1; n=24, 22	-3.25 Kilograms Standard Deviation 3.078	-2.61 Kilograms Standard Deviation 4.200
Change From Baseline in Weight CYCLE 7 DAY 1; n=24, 22	-3.75 Kilograms Standard Deviation 4.172	-2.14 Kilograms Standard Deviation 5.877
Change From Baseline in Weight CYCLE 8 DAY 1; n=22, 21	-3.89 Kilograms Standard Deviation 4.384	-2.61 Kilograms Standard Deviation 5.016
Change From Baseline in Weight CYCLE 9 DAY 1; n=19, 16	-4.14 Kilograms Standard Deviation 5.151	-2.14 Kilograms Standard Deviation 4.998
Change From Baseline in Weight CYCLE 10 DAY 1; n=18, 16	-5.50 Kilograms Standard Deviation 6.983	-1.99 Kilograms Standard Deviation 5.478
Change From Baseline in Weight CYCLE 11 DAY 1; n=16, 15	-5.70 Kilograms Standard Deviation 6.045	-1.67 Kilograms Standard Deviation 4.681
Change From Baseline in Weight CYCLE 12 DAY 1; n=15, 13	-5.85 Kilograms Standard Deviation 5.206	-1.72 Kilograms Standard Deviation 4.260
Change From Baseline in Weight CYCLE 13 DAY 1; n=13, 12	-6.54 Kilograms Standard Deviation 5.795	-1.11 Kilograms Standard Deviation 4.483
Change From Baseline in Weight CYCLE 14 DAY 1; n=12, 12	-7.03 Kilograms Standard Deviation 6.500	-1.23 Kilograms Standard Deviation 3.899
Change From Baseline in Weight CYCLE 15 DAY 1; n=10, 9	-7.21 Kilograms Standard Deviation 7.449	-1.09 Kilograms Standard Deviation 4.705
Change From Baseline in Weight CYCLE 16 DAY 1; n=10, 9	-7.59 Kilograms Standard Deviation 6.970	-0.93 Kilograms Standard Deviation 4.519
Change From Baseline in Weight CYCLE 17 DAY 1; n=8, 8	-8.49 Kilograms Standard Deviation 8.606	-1.24 Kilograms Standard Deviation 5.205
Change From Baseline in Weight CYCLE 18 DAY 1; n=8, 8	-8.25 Kilograms Standard Deviation 9.002	-0.80 Kilograms Standard Deviation 4.888
Change From Baseline in Weight CYCLE 19 DAY 1; n=6, 8	-8.78 Kilograms Standard Deviation 9.953	-0.19 Kilograms Standard Deviation 5.044
Change From Baseline in Weight CYCLE 20 DAY 1; n=6, 8	-9.22 Kilograms Standard Deviation 10.752	-0.40 Kilograms Standard Deviation 5.986
Change From Baseline in Weight CYCLE 22 DAY 1; n=4, 8	-3.50 Kilograms Standard Deviation 7.735	-0.32 Kilograms Standard Deviation 5.370
Change From Baseline in Weight CYCLE 23 DAY 1; n=4, 8	-4.13 Kilograms Standard Deviation 8.189	-0.16 Kilograms Standard Deviation 5.297
Change From Baseline in Weight CYCLE 24 DAY 1; n=4, 7	-3.38 Kilograms Standard Deviation 7.273	-1.93 Kilograms Standard Deviation 1.511
Change From Baseline in Weight CYCLE 25 DAY 1; n=4, 8	-3.88 Kilograms Standard Deviation 8.250	0.04 Kilograms Standard Deviation 5.789
Change From Baseline in Weight CYCLE 26 DAY 1; n=4, 7	-3.88 Kilograms Standard Deviation 6.981	0.54 Kilograms Standard Deviation 6.484
Change From Baseline in Weight CYCLE 27 DAY 1; n=4, 5	-4.88 Kilograms Standard Deviation 6.408	-2.04 Kilograms Standard Deviation 2.308
Change From Baseline in Weight CYCLE 28 DAY 1; n=4, 5	-5.13 Kilograms Standard Deviation 6.115	-2.20 Kilograms Standard Deviation 1.989
Change From Baseline in Weight CYCLE 29 DAY 1; n=3, 4	-5.50 Kilograms Standard Deviation 7.697	-2.18 Kilograms Standard Deviation 1.786
Change From Baseline in Weight CYCLE 30 DAY 1; n=3, 4	-5.83 Kilograms Standard Deviation 7.286	-3.25 Kilograms Standard Deviation 0.379
Change From Baseline in Weight CYCLE 31 DAY 1; n=3, 4	-5.50 Kilograms Standard Deviation 7.467	-3.38 Kilograms Standard Deviation 0.435
Change From Baseline in Weight CYCLE 32 DAY 1; n=3, 4	-5.50 Kilograms Standard Deviation 7.467	-3.05 Kilograms Standard Deviation 0.100
Change From Baseline in Weight CYCLE 33 DAY 1; n=2, 4	-1.75 Kilograms Standard Deviation 1.061	-3.13 Kilograms Standard Deviation 0.150
Change From Baseline in Weight CYCLE 34 DAY 1; n=1, 4	-2.50 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	-3.18 Kilograms Standard Deviation 0.350
Change From Baseline in Weight CYCLE 35 DAY 1; n=0, 4	—	-3.25 Kilograms Standard Deviation 0.379
Change From Baseline in Weight CYCLE 36 DAY 1; n=0, 4	—	-3.38 Kilograms Standard Deviation 0.624
Change From Baseline in Weight CYCLE 37 DAY 1; n=0, 3	—	-3.17 Kilograms Standard Deviation 0.961
Change From Baseline in Weight CYCLE 38 DAY 1; n=0, 3	—	-2.63 Kilograms Standard Deviation 0.814
Change From Baseline in Weight CYCLE 39 DAY 1; n=0, 3	—	-3.00 Kilograms Standard Deviation 0.200
Change From Baseline in Weight CYCLE 40 DAY 1; n=0, 2	—	-3.40 Kilograms Standard Deviation 0.566
Change From Baseline in Weight CYCLE 41 DAY 1; n=0, 2	—	-2.90 Kilograms Standard Deviation 0.141
Change From Baseline in Weight CYCLE 42 DAY 1; n=0, 2	—	-3.00 Kilograms Standard Deviation 0.000
Change From Baseline in Weight CYCLE 43 DAY 1; n=0, 2	—	-2.90 Kilograms Standard Deviation 0.141
Change From Baseline in Weight CYCLE 44 DAY 1; n=0, 2	—	-3.90 Kilograms Standard Deviation 1.273
Change From Baseline in Weight CYCLE 45 DAY 1; n=0, 2	—	-4.40 Kilograms Standard Deviation 1.980
Change From Baseline in Weight CYCLE 46 DAY 1; n=0, 2	—	-3.90 Kilograms Standard Deviation 1.273
Change From Baseline in Weight CYCLE 47 DAY 1; n=0, 2	—	-3.40 Kilograms Standard Deviation 0.566
Change From Baseline in Weight CYCLE 48 DAY 1; n=0, 2	—	-3.65 Kilograms Standard Deviation 0.919
Change From Baseline in Weight CYCLE 49 DAY 1; n=0, 2	—	-4.40 Kilograms Standard Deviation 1.980
Change From Baseline in Weight CYCLE 50 DAY 1; n=0, 2	—	-4.15 Kilograms Standard Deviation 1.626
Change From Baseline in Weight CYCLE 51 DAY 1; n=0, 2	—	-3.65 Kilograms Standard Deviation 0.919
Change From Baseline in Weight CYCLE 52 DAY 1; n=0, 2	—	-2.90 Kilograms Standard Deviation 0.141
Change From Baseline in Weight CYCLE 53 DAY 1; n=0, 2	—	-4.40 Kilograms Standard Deviation 1.980
Change From Baseline in Weight CYCLE 54 DAY 1; n=0, 2	—	-3.65 Kilograms Standard Deviation 0.919
Change From Baseline in Weight CYCLE 55 DAY 1; n=0, 1	—	-2.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 56 DAY 1; n=0, 1	—	-1.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 57 DAY 1; n=0, 1	—	-0.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 58 DAY 1; n=0, 1	—	-1.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 59 DAY 1; n=0, 1	—	-0.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 60 DAY 1; n=0, 1	—	-0.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 61 DAY 1; n=0, 1	—	0.00 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 62 DAY 1; n=0, 1	—	-0.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 63 DAY 1; n=0, 1	—	-0.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 64 DAY 1; n=0, 1	—	-0.60 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 65 DAY 1; n=0, 1	—	-2.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 66 DAY 1; n=0, 1	—	-3.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 67 DAY 1; n=0, 1	—	-3.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 68 DAY 1; n=0, 1	—	-1.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 69 DAY 1; n=0, 1	—	-1.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 70 DAY 1; n=0, 1	—	0.20 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 71 DAY 1; n=0, 1	—	-0.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 72 DAY 1; n=0, 1	—	-0.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 73 DAY 1; n=0, 1	—	-1.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 74 DAY 1; n=0, 1	—	-0.80 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.
Change From Baseline in Weight CYCLE 75 DAY 1; n=0, 1	—	-0.30 Kilograms Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.

SECONDARY outcome

Timeframe: Day1 pre-dose(Cycle 1,2,4,5,6,8,9,10,12,14,16,17,18,20,22,24,26,28,30,32,34);end of infusion (Cycle 1);Day8 pre-dose(Cycle 1);Day15 pre-dose (Cycle 1,2);Day21(Cycle 2,4,6,8,9,12,14,16,18,20,22,24,26,28,30,32,34);Cycle 99(end of treatment) (21-day cycles)

Population: As Treated Population. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles)

Blood samples were collected for determination of serum mapatumumab concentration at the indicated time points. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time points.

Outcome measures

Outcome measures
Measure	Sorafenib+Placebo n=50 Participants Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity	Sorafenib+Mapatumumab 30 mg/kg Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
Serum Concentration of Mapatumumab CYCLE 1 Day 1, pre-dose, n=46	638.4 Nanograms per milliliter Standard Deviation 2668.01	—
Serum Concentration of Mapatumumab CYCLE 1 DAY 1,end of infusion, n=46	555157.6 Nanograms per milliliter Standard Deviation 260848.85	—
Serum Concentration of Mapatumumab CYCLE 1; DAY 8, pre-dose; n=40	250229.9 Nanograms per milliliter Standard Deviation 89714.76	—
Serum Concentration of Mapatumumab CYCLE 1 DAY 15, pre-dose; n=1	121556.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 2 DAY 1, pre-dose; n=40	126588.4 Nanograms per milliliter Standard Deviation 149231.45	—
Serum Concentration of Mapatumumab CYCLE 2 DAY 15, pre-dose; n=3	128839.0 Nanograms per milliliter Standard Deviation 153667.78	—
Serum Concentration of Mapatumumab CYCLE 2 DAY 21; n=28	180606.6 Nanograms per milliliter Standard Deviation 109893.28	—
Serum Concentration of Mapatumumab CYCLE 4 DAY 1, pre-dose; n=31	194936.8 Nanograms per milliliter Standard Deviation 142242.80	—
Serum Concentration of Mapatumumab CYCLE 4, DAY 21; n=23	183754.3 Nanograms per milliliter Standard Deviation 93584.71	—
Serum Concentration of Mapatumumab CYCLE 5, DAY 1, pre-dose; n=1	223681.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 6, DAY 1, pre-dose; n=21	160741.5 Nanograms per milliliter Standard Deviation 64893.03	—
Serum Concentration of Mapatumumab CYCLE 6, DAY 21; n=20	201237.7 Nanograms per milliliter Standard Deviation 75352.54	—
Serum Concentration of Mapatumumab CYCLE 8, DAY 1, pre-dose; n=21	246616.5 Nanograms per milliliter Standard Deviation 204363.04	—
Serum Concentration of Mapatumumab CYCLE 8, DAY 21; n=17	187927.6 Nanograms per milliliter Standard Deviation 104803.16	—
Serum Concentration of Mapatumumab CYCLE 9, DAY 1, pre-dose; n=1	136122.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 10, DAY 1, pre-dose; n=16	204147.1 Nanograms per milliliter Standard Deviation 103243.21	—
Serum Concentration of Mapatumumab CYCLE 10, DAY 21; n=15	219503.0 Nanograms per milliliter Standard Deviation 105968.15	—
Serum Concentration of Mapatumumab CYCLE 12, DAY 1, pre-dose; n=12	200141.1 Nanograms per milliliter Standard Deviation 93093.68	—
Serum Concentration of Mapatumumab CYCLE 12, DAY 21; n=11	256924.5 Nanograms per milliliter Standard Deviation 111904.82	—
Serum Concentration of Mapatumumab CYCLE 14, DAY 1, pre-dose; n=9	207930.6 Nanograms per milliliter Standard Deviation 84247.04	—
Serum Concentration of Mapatumumab CYCLE 14, DAY 21 n=9	256779.4 Nanograms per milliliter Standard Deviation 127463.67	—
Serum Concentration of Mapatumumab CYCLE 16, DAY 1, pre-dose; n=9	196074.3 Nanograms per milliliter Standard Deviation 100377.45	—
Serum Concentration of Mapatumumab CYCLE 16, DAY 21; n=8	253521.0 Nanograms per milliliter Standard Deviation 87675.77	—
Serum Concentration of Mapatumumab CYCLE 17, DAY 1, pre-dose; n=1	156161.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 18, DAY 1, pre-dose; n=8	199379.4 Nanograms per milliliter Standard Deviation 61011.54	—
Serum Concentration of Mapatumumab CYCLE 18, DAY 21; n=7	229539.1 Nanograms per milliliter Standard Deviation 86440.46	—
Serum Concentration of Mapatumumab CYCLE 20 DAY 1, pre-dose; n=8	189486.6 Nanograms per milliliter Standard Deviation 54097.82	—
Serum Concentration of Mapatumumab CYCLE 20, DAY 21; n=7	222443.7 Nanograms per milliliter Standard Deviation 86046.38	—
Serum Concentration of Mapatumumab CYCLE 22 DAY 1, pre-dose; n=8	208485.4 Nanograms per milliliter Standard Deviation 80252.29	—
Serum Concentration of Mapatumumab CYCLE 22, DAY 21; n=7	212481.1 Nanograms per milliliter Standard Deviation 110103.79	—
Serum Concentration of Mapatumumab CYCLE 24 DAY 1, pre-dose; n=8	219439.8 Nanograms per milliliter Standard Deviation 71740.01	—
Serum Concentration of Mapatumumab CYCLE 24, DAY 21; n=7	221249.1 Nanograms per milliliter Standard Deviation 73317.41	—
Serum Concentration of Mapatumumab CYCLE 26 DAY 1, pre-dose; n=4	223427.3 Nanograms per milliliter Standard Deviation 67101.56	—
Serum Concentration of Mapatumumab CYCLE 26, DAY 21; n=4	295941.5 Nanograms per milliliter Standard Deviation 100208.45	—
Serum Concentration of Mapatumumab CYCLE 28 DAY 1, pre-dose; n=3	219802.7 Nanograms per milliliter Standard Deviation 115484.98	—
Serum Concentration of Mapatumumab CYCLE 28, DAY 21; n=2	173018.5 Nanograms per milliliter Standard Deviation 54870.78	—
Serum Concentration of Mapatumumab CYCLE 30 DAY 1, pre-dose; n=2	173200.5 Nanograms per milliliter Standard Deviation 13447.05	—
Serum Concentration of Mapatumumab CYCLE 30, DAY 21; n=2	180484.5 Nanograms per milliliter Standard Deviation 14783.48	—
Serum Concentration of Mapatumumab CYCLE 32 DAY 1, pre-dose; n=1	178275.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 32, DAY 21; n=1	177496.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 34 DAY 1, pre-dose; n=1	150553.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 34, DAY 21; n=1	134781.0 Nanograms per milliliter Standard Deviation NA Standard deviation could not be calculated as only one participant was analyzed at the specified time point.	—
Serum Concentration of Mapatumumab CYCLE 99, end of treatment; n=14	86640.1 Nanograms per milliliter Standard Deviation 64981.14	—

Adverse Events

Sorafenib+Placebo

Serious events: 27 serious events

Other events: 47 other events

Deaths: 40 deaths

Sorafenib+Mapatumumab 30 mg/kg

Serious events: 21 serious events

Other events: 49 other events

Deaths: 39 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER